The overall objective of our research program involves the development of general, broadly applicable methods for the synthesis of novel heterocyclic systems. Emphasis is placed on the use of cycloaddition chemistry for the construction of a variety of biologically interesting molecules. Among the reactions to be studied are [4+2]-cycloaddition reactions of amido and thio-substituted furans and other heteroaromatics as a method for preparing novel azapolycyclic rings. The project will also focus on using a variety of novel thio reagents for intramolecular cyclization. A number of inter-and intramolecular variations of the tandem sequence will be explored which will provide access to the structural frameworks contained within the Amaryllidaceae, Aspidosperma, Erythrina, Sceletium, iboga, Ergot, Vinca and Strychnos alkaloids. These complex nitrogen containing substrates are of interest as synthetic targets due to the wide range of biological properties they exhibit. A variety of pharmacological effects, including sedative, hypotensive, neuromuscular blocking, CNS depressant and skin disorder properties are associated with these compounds. The various synthetic strategies outlined in the proposal will lead to the rapid assembly of the basic core skeleton of various alkaloids and will provide quantities of material for detailed biological assay. The generation of biologically active compounds by new synthetic methods remains an important part of both health related and chemical research.